Dichloromethane → [2-Chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]cyclopentylamine

HRID 2359531Notes

Reaction equation

HRID 2359531 reaction equation
Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ClCCl.CCN(CC)CC.[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[CH:30])[CH3:26]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]([C:30]#[C:29][CH:28]([O:31][CH2:32][CH3:33])[O:27][CH2:25][CH3:26])=[CH:7][N:6]=1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 8471TriethylamineHCID 662853,3-DiethoxypropyneHCID 442482475-Bromo-2-chloro-N-cyclopentyl-4-pyrimidinamine

Product 1

HCID 58315397[2-Chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]cyclopentylamineYield 54.3%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a stirred solution of (5-bromo-2-chloro pyrimidin-4-yl)-cyclopentyl-amine (1.00 g, 3.62 mmol) and PdCl2(dppf).dichloromethane (148 mg, 0.181 mmol) in THF (10 mL) is added Et3N (0.757 mL, 5.43 mmol) and 3,3-diethoxy-propyne (0.778 mL, 5.43 mmol) sequentially at room temperature. The mixture is degassed under a stream of N2 and stirred at room temperature for 10 minutes before CuI (29 mg, 0.154 mmol) is added. The reaction vessel is evacuated and back-filled with N2 (×3) and heated at 60° C. for 48 hours. The mixture is allowed to cool, diluted with EtOAc, filtered and partitioned between H2O and ethyl acetate. The phases are separated and the aqueous layer is further extracted with EtOAc (×3), combined organic extracts are dried (MgSO4), filtered and concentrated. The residue is purified by SiO2 chromatography, eluting with a gradient of 5% EtOAc/petrol to 20% EtOAc/petrol to give [2-chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]-cyclopentyl amine (636 mg, 54%). MS (ESI) m/z 324.2 (M+H)+

Workup

  1. customThe mixture is degassed under a stream of N2
  2. additionis added
  3. customThe reaction vessel is evacuated
  4. additionback-filled with N2 (×3)
  5. temperatureto cool
  6. additiondiluted with EtOAc
  7. filtrationfiltered
  8. custompartitioned between H2O and ethyl acetate
  9. customThe phases are separated
  10. extractionthe aqueous layer is further extracted with EtOAc (×3)
  11. dry with materialare dried (MgSO4)
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe residue is purified by SiO2 chromatography
  15. washeluting with a gradient of 5% EtOAc/petrol to 20% EtOAc/petrol

Sources & evidence

ORD record
ord-61ea82a8345a4d098e0af3aee184159c
Source dataset
uspto-grants-2014_04
Patent number
US08685980B2

Reaction notes

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